Noncovalent Peptide Stapling Using Alpha-Methyl-l-Phenylalanine for a-Helical Peptidomimetics
Por:
Bathgate R, Praveen P, Sethi A, Furuya W, Dhingra R, Kocan M, Ou Q, Valkovic A, Gil-Miravet I, Navarro-Sánchez M, Olucha-Bordonau F, Gundlach A, Rosengren K, Gooley P, Dutschmann M, Hossain M
Publicada:
13 jul 2023
Ahead of Print:
1 jul 2023
Resumen:
Peptides and peptidomimetics are attractive drug candidatesbecauseof their high target specificity and low-toxicity profiles. Developingpeptidomimetics using hydrocarbon (HC)-stapling or other staplingstrategies has gained momentum because of their high stability andresistance to proteases; however, they have limitations. Here, wetake advantage of the & alpha;-methyl group and an aromatic phenylring in a unique unnatural amino acid, & alpha;-methyl-l-phenylalanine(& alpha;F), and propose a novel, noncovalent stapling strategy tostabilize peptides. We utilized this strategy to create an & alpha;-helicalB-chain mimetic of a complex insulin-like peptide, human relaxin-3(H3 relaxin). Our comprehensive data set (in vitro, ex vivo, and in vivo) confirmedthat the new high-yielding B-chain mimetic, H3B10-27(13/17 & alpha;F),is remarkably stable in serum and fully mimics the biological functionof H3 relaxin. H3B10-27(13/17 & alpha;F) is an excellent scaffold forfurther development as a drug lead and an important tool to decipherthe physiological functions of the neuropeptide G protein-coupledreceptor, RXFP3.
Filiaciones:
Bathgate R:
Univ Melbourne, Florey, Parkville, Vic 3052, Australia
Univ Melbourne, Dept Biochem & Pharmacol, Parkville, Vic 3052, Australia
Praveen P:
Univ Melbourne, Florey, Parkville, Vic 3052, Australia
Sethi A:
Univ Melbourne, Dept Biochem & Pharmacol, Parkville, Vic 3052, Australia
Australian Nucl Sci Technol Org, Australian Synchrotron, Clayton, Vic 3168, Australia
Furuya W:
Univ Melbourne, Florey, Parkville, Vic 3052, Australia
Dhingra R:
Univ Melbourne, Florey, Parkville, Vic 3052, Australia
Univ Melbourne, Florey Dept Neurosci & Mental Hlth, Parkville, Vic 3052, Australia
Kocan M:
Univ Melbourne, Florey, Parkville, Vic 3052, Australia
Ou Q:
Univ Melbourne, Florey, Parkville, Vic 3052, Australia
Valkovic A:
Univ Melbourne, Florey, Parkville, Vic 3052, Australia
Gil-Miravet I:
Univ Jaume 1, Fac Hlth Sci, Predept Unit Med, Castellode La Plana 12071, Spain
Navarro-Sánchez M:
Univ Jaume 1, Fac Hlth Sci, Predept Unit Med, Castellode La Plana 12071, Spain
Olucha-Bordonau F:
Univ Jaume 1, Fac Hlth Sci, Predept Unit Med, Castellode La Plana 12071, Spain
Gundlach A:
Univ Melbourne, Florey, Parkville, Vic 3052, Australia
Univ Melbourne, Florey Dept Neurosci & Mental Hlth, Parkville, Vic 3052, Australia
Univ Melbourne, Florey Dept Neurosci & Mental Hlth, Florey, Parkville, Vic 3052, Australia
Univ Melbourne, Dept Anat & Physiol, Parkville, Vic 3052, Australia
Rosengren K:
Univ Queensland, Sch Biomed Sci, St Lucia, Qld 4072, Australia
Gooley P:
Univ Melbourne, Dept Biochem & Pharmacol, Parkville, Vic 3052, Australia
Univ Melbourne, Bio21 Mol Sci & Biotechnol, Parkville, Vic 3052, Australia
Dutschmann M:
Univ Melbourne, Florey, Parkville, Vic 3052, Australia
Univ Melbourne, Florey Dept Neurosci & Mental Hlth, Parkville, Vic 3052, Australia
Hossain M:
Univ Melbourne, Florey, Parkville, Vic 3052, Australia
Univ Melbourne, Florey Dept Neurosci & Mental Hlth, Parkville, Vic 3052, Australia
Univ Melbourne, Sch Chem, Parkville, Vic 3052, Australia
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